Combination of dpp iv inhibitor and a cardiovascular compound

ABSTRACT

The present invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising of a DPP IV inhibitor or a pharmaceutically acceptable salt thereof and a cardiovascular compound (being different from a statin) or a pharmaceutically acceptable salt thereof. The present invention furthermore relates to the use of such a combination for the prevention, delay of progression or treatment of diseases and disorders selected from the group consisting of hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetes, especially type 2 diabetes mellitus, diabetic retinophathy, macular degeneration, cataract, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, syndrome X, premenstrual syndrome, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertryglyceridemia, insulin resistance, impaired glucose metabolism, conditions of impaired glucose tolerance, conditions of impaired fasting plasma glucose, obesity, erectile dysfunction, skin and connective tissue disorders, foot ulcerations and ulcerative colitis, endothelial dysfunction and impaired vascular compliance.

The present invention relates to a combination, such as a combinedpreparation or pharmaceutical composition, respectively, comprising of aDPP IV inhibitor or a pharmaceutically acceptable salt thereof and acardiovascular compound (being different from a statin) or apharmaceutically acceptable salt thereof.

The invention especially relates to a combination, such as a combinedpreparation or pharmaceutical composition, respectively, comprising aDPP IV inhibitor or a pharmaceutically acceptable salt thereof and atleast one cardiovascular compound, i.e. a therapeutic agent selectedfrom the group consisting of

(i) an AT₁-receptor antagonist or a pharmaceutically acceptable saltthereof,

(ii) an angiotensin converting enzyme (ACE) inhibitor or apharmaceutically acceptable salt thereof,

(iii) a renin inhibitor or a pharmaceutically acceptable salt thereof,

(iv) a beta adrenergic receptor blocker or a pharmaceutically acceptablesalt thereof,

(v) an alpha adrenergic receptor blocker or a pharmaceuticallyacceptable salt thereof,

(vi) a calcium channel blocker or a pharmaceutically acceptable saltthereof,

(vii) an aldosterone synthase inhibitor or a pharmaceutically acceptablesalt thereof,

(viii) an aldosterone receptor antagonist or a pharmaceuticallyacceptable salt thereof,

(ix) a neutral endopeptidase (NEP) inhibitor or a pharmaceuticallyacceptable salt thereof,

(x) a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP)inhibitor or a pharmaceutically acceptable salt thereof,

(xi) an endothelin receptor antagonist or a pharmaceutically acceptablesalt thereof,

(xii) a diuretic or a pharmaceutically acceptable salt thereof.

The term “at least one therapeutic agent” shall mean that in addition tothe compound of formula (I) one or more, for example two, furthermorethree, active ingredients as specified according to the presentinvention can be combined.

The term “DPP-IV” as used herein is intended to mean dipeptidylpeptidase IV, also known as CD26. DPP-IV, a serine protease belonging tothe group of post- proline/alanine cleaving amino-dipeptidases,specifically removes the two N-terminal amino acids from proteins havingproline or alanine in position 2. DPP-IV can be used in the control ofglucose metabolism because its substrates include the insulinotropichormones glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide(GIP). GLP-1 and GIP are active only in their intact forms; removal oftheir two N-terminal amino acids inactivates them.

In vivo administration of synthetic inhibitors of DPP-IV preventsN-terminal degradation of GLP-1 and GIP, resulting in higher plasmaconcentrations of these hormones, increased insulin secretion and,therefore, improved glucose tolerance.

The term “DPP-IV inhibitor” is intended to indicate a molecule thatexhibits inhibition of the enzymatic activity of DPP-IV and functionallyrelated enzymes, such as from 1-100% inhibition, and specially preservesthe action of substrate molecules, including but not limited to GLP-1,GIP, peptide histidine methionine, substance P, neuropeptide Y, andother molecules typically containing alanine or proline residues in thesecond amino terminal position. Treatment with DPP-IV inhibitorsprolongs the duration of action of peptide substrates and increaseslevels of their intact, undegraded forms leading to a spectrum ofbiological activities relevant to the disclosed invention.

For that purpose, chemical compounds are tested for their ability toinhibit the enzyme activity of purified CD26/DPP-IV. Briefly, theactivity of CD26/DPP-IV is measured in vitro by its ability to cleavethe synthetic substrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavageof Gly-Pro-pNA by DPP-IV liberates the product p-nitroanilide (pNA),whose rate of appearance is directly proportional to the enzymeactivity. Inhibition of the enzyme activity by specific enzymeinhibitors slows down the generation of pNA. Stronger interactionbetween an inhibitor and the enzyme results in a slower rate ofgeneration of pNA. Thus, the degree of inhibition of the rate ofaccumulation of pNA is a direct measure of the strength of enzymeinhibition. The accumulation of pNA is measured spectrophotometrically.The inhibition constant, Ki, for each compound is determined byincubating fixed amounts of enzyme with several different concentrationsof inhibitor and substrate.

In the present context “a DPP-IV inhibitor” is also intended to compriseactive metabolites and prodrugs thereof, such as active metabolites andprodrugs of DPP-IV inhibitors. An active “metabolite” is an activederivative of a DPP-IV inhibitor produced when the DPP-IV inhibitor ismetabolized. A “prodrug” is a compound that is either metabolized to aDPP-IV inhibitor or is metabolized to the same metabolite(s) as a DPP-IVinhibitor.

DPP-IV inhibitors are known in the art. For example, DPP-IV inhibitorsare in each case generically and specifically disclosed e.g. in WO98/19998,DE19616 486 A1, WO 00/34241, WO 95/15309, WO 01/72290,WO01/52825, WO 9310127, WO 9925719, WO 9938501, WO 9946272, WO 9967278and WO 9967279. In each case in particular in the compound claims andthe final products of the working examples, the subject matter of thefinal products, the pharmaceutical preparations and the claims arehereby incorporated into the present application by reference to thesepublications.

Published patent application WO 9819998 discloses N- (N′-substitutedglycyl)-2-cyano pyrrolidines, in particular 1-[2-[5-Cyanopyridin-2-yl]amino]-ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728).

DE19616 486 A1 discloses val-pyr, val-thiazolidide,isoleucyl-thiazolidide, isoleucyl-pyrrolidide, and fumar salts ofisoleucyl-thiazolidide and isoleucyl-pyrrolidide.

Published patent application WO 0034241 and published patent U.S. Pat.No. 6,110,949 disclose N-substituted adamantyl-amino-acetyl-2-cyanopyrrolidines and W (substituted glycyl)-4-cyano pyrrolidinesrespectively. DPP-IV inhibitors of interest are specially those cited inclaims 1 to 4.

Published patent application WO 9515309 discloses amino acid2-cyanopyrrolidine amides as inhibitors of DPP-IV Published patentapplication WO 9529691 discloses peptidyl derivates of diesters ofalpha-aminoalkylphosphonic acids, particularly those with proline orrelated structures. DPP-IV inhibitors of interest are specially thosecited in Table 1 to 8.

In WO 01/72290 DPP-IV inhibitors of interest are specially those citedin example 1 and claims 1, 4, and 6.

WO01/52825 specially discloses(S)-1-{2-[5-cyanopyridin-2yl)amino]ethyl-aminoacetyl)-2-cyano-pyrrolidineor (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine.

Published patent application WO 9310127 discloses proline boronic estersuseful as DPP-IV inhibitors. DPP-IV inhibitors of interest are speciallythose cited in examples 1 to 19.

Published patent application WO 9925719 discloses sulphostin, a DPP-IVinhibitor prepared by culturing a Streptomyces microorganism.

Published patent application WO 9938501 discloses N-substituted 4-8membered heterocyclic rings. DPP-IV inhibitors of interest are speciallythose cited in claims 15 to 20

Published patent application WO 9946272 discloses phosphoric compoundsas inhibitors of DPP-IV. DPP-IV inhibitors of interest are speciallythose cited in claims 1 to 23.

Published patent applications WO 9967278 and WO 9967279 disclose DPP-IVprodrugs and inhibitors of the form A-B-C where C is either a stable orunstable inhibitor of DPP-IV. Any of the substances disclosed in theabove mentioned patent documents, hereby included by reference, areconsidered potentially useful as DPP-IV inhibitors to be used incarrying out the present invention.

Preferred DPP-IV inhibitors are N-substitutedadamantyl-amino-acetyl-2-cyano pyrrolidines, N (substitutedglycyl)-4-cyano pyrrolidines, N- (N′-substitutedglycyl)-2-cyanopyrrolidines, N-aminoacyl thiazolidines, N-aminoacylpyrrolidines, L-allo-isoleucyl thiazolidine, L-threo-isoleucylpyrrolidine, and L-allo-isoleucyl pyrrolidine,1-[2-[(5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidineand pharmaceutical salts thereof.

Especially preferred are1-{2-[(5-cyanopyridin-2-yl)amino]ethylamino}acetyl-2(S)-cyano-pyrrolidinedihydrochloride, of formula

especially the dihydrochloride thereof, and pyrrolidine,1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-, (S) of formula

L-threo-isoleucyl thiazolidine (compound code according to Probiodrug:P32/98), and pharmaceutical salts thereof.

Especially preferred are orally active DPP-IV inhibitors.

AT₁-receptor antagonists (also called angiotensin II receptorantagonists or angiotensin II receptor blockers) are understood to bethose active ingredients that bind to the AT₁-receptor subtype ofangiotensin II receptor but do not result in activation of the receptor.As a consequence of the inhibition of the AT₁ receptor, theseantagonists can, for example, be employed as antihypertensives or fortreating congestive heart failure.

The class of AT₁ receptor antagonists comprises compounds havingdiffering structural features, essentially preferred are thenon-peptidic ones. For example, mention may be made of the compoundsthat are selected from the group consisting of valsartan (cf. EP443983), losartan (cf. EP253310), candesartan (cf. 459136), eprosartan(cf. EP 403159), irbesartan (cf. EP454511), olmesartan (cf. EP 503785),tasosartan (cf. EP539086), telmisartan (cf. EP 522314), saprisartan, thecompound with the designation E-1477 of the following formula

the compound with the designation SC-52458 of the following formula

and the compound with the designation the compound ZD-8731 of thefollowing formula

or, in each case, a pharmaceutically acceptable salt thereof.

Preferred AT₁-receptor antagonist are those agents that have beenmarketed, most preferred is valsartan or a pharmaceutically acceptablesalt thereof.

The interruption of the enzymatic degradation of angiotensin I toangiotensin II with so-called ACE-inhibitors (also called angiotensinconverting enzyme inhibitors) is a successful variant for the regulationof blood pressure and also a therapeutic method for the treatment ofcongestive heart failure.

The class of ACE inhibitors comprises compounds having differingstructural features. For example, mention may be made of the compoundswhich are selected from the group consisting alacepril, benazepril,benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril,enalaprilat, fosinopril, imidapril, lisinopril, moexipril, moveltopril,pentopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat,spirapril, temocapril, trandolapril and zofenopril, or, in each case, apharmaceutically acceptable salt thereof.

Preferred ACE inhibitors are those agents that have been marketed, mostpreferred are benazepril, ramipril, lisinopril and enalapril.

Renin released from the kidneys cleaves angiotensinogen in thecirculation to form the decapeptide angiotensin I. This is in turncleaved by angiotensin converting enzyme in the lungs, kidneys and otherorgans to form the octapeptide angiotensin II. The octapeptide increasesblood pressure both directly by arterial vasoconstriction and indirectlyby liberating from the adrenal glands the sodium-ion-retaining hormonealdosterone, accompanied by an increase in extracellular fluid volume.Inhibitors of the enzymatic activity of renin bring about a reduction inthe formation of angiotensin I. As a result a smaller amount ofangiotensin II is produced. The reduced concentration of that activepeptide hormone is the direct cause of e.g. the antihypertensive effectof renin inhibitors. Accordingly, renin inhibitors or salts thereof canbe employed e.g. as antihypertensives or for treating congestive heartfailure.

The class of renin inhibitors comprises compounds having differingstructural features. For example, mention may be made of compounds whichare selected from the group consisting of ditekiren (chemical name:[1S-[1R*,2R*,4R*(1R*,2R*)]]-1-[(1,1-dimethylethoxy)carbonyl]-L-prolyI-L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmrthyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alfa-methyl-L-histidinamide);terlakiren (chemical name:[R-(R*,S*)]-N-(4-morpholinylcarbonyl)-L-phenylalanyl-N-[1-(cyclohexyImethyl)-2-hydroxy-3-(1-methylethoxy)-3-oxopropyl]-S-methyl-L-cysteineamide);zankiren (chemical name:[1S-[1R*[R*(R*)],2S*,3R*]]-N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-alfa-[[2-[[(4-methyl-1-piperazinyl)sulfonyl]methyl]-1-oxo-3-phenylpropyl]amino]-4thiazolepropanamide),especially the hydrochloride thereof; RO 66-1132 and RO-66-1168 offormulae

respectively.

Especially preferred is the compound of formula

chemically defined as2(S),4(S),5(S),7(S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(1-methylethyl)-4-hydroxy-5-amino-8-[4-methoxy-3(3-methoxy-propoxy)phenyl]-octanamide(generic name: aliskiren), specifically disclosed in EP 678503 A, or apharmaceutically acceptable salt, especially the hemi-fumarate, thereof.

A beta adrenergic receptor blocker in said combination preferably is arepresentative selected from the group consisting of a selectiveβ1-blocker, such as atenolol, bisoprolol (especially the fumaratethereof), metoprolol (especially the hemi-(R,R)fumarate or fumaratethereof), esmolol (especially the hydrochloride thereof, celiprolol(especially the hydrochloride thereof), betaxolol (especially thehydrochloride thereof) or taliprolol, or, a non-selective β-blocker,such as oxprenolol (especially the hydrochloride thereof), pindolol,propranolol (especially the hydrochloride thereof), timolol (especiallythe maleate thereof), bupranolol (especially the hydrochloride thereof),penbutolol (especially the sulphate thereof), mepindolol (especially thesulphate thereof), carteolol (especially the hydrochloride thereof) ornadolol, and a β-blocker with α-blocking activity such as carvedilol orlabetalol; or in each case, a pharmaceutically acceptable salt thereof.

An alpha₁ adrenergic receptor blocker in said combination preferably isa representative selected from the group consisting of doxazosin,prazosin or terazosin; or in each case, a pharmaceutically acceptablesalt thereof. All of these alpha₁ adrenergic receptor blockers are usedas antihypertensive drugs.

The class of calcium channel blockers (CCBs) essentially comprisesdihydropyridines (DHPs) and non-DHPs such as diltiazem-type andverapamil-type CCBs. A CCB useful in said combination is preferably aDHP representative selected from the group consisting of amlodipine,felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine,niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, andnivaldipine, and is preferably a non-DHP representative selected fromthe group consisting of flunarizine, prenylamine, diltiazem, fendiline,gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in eachcase, a pharmaceutically acceptable salt thereof. All these CCBs aretherapeutically used, e.g. as anti-hypertensive, anti-angina pectoris oranti-arrhythmic drugs.

Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine,nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or,e.g. dependent on the specific CCB, a pharmaceutically acceptable saltthereof. An especially preferred DHP is amlodipine or a pharmaceuticallyacceptable salt, especially the besylate, thereof. An especiallypreferred representative of non-DHPs is verapamil or a pharmaceuticallyacceptable salt, especially the hydrochloride, thereof.

Aldosterone synthase is an enzyme that converts corticosterone toaldosterone by hydroxylating corticosterone to form 18-OH-corticosteroneand 18OH-corticosterone to aldosterone. The class of aldosteronesynthase inhibitors is known to be applied for the treatment ofhypertension and primary aldosteronism comprises both steroidal andnon-steroidal aldosterone synthase inhibitors, the later being mostpreferred.

Preference is given to commercially available aldosterone synthaseinhibitors or those aldosterone synthase inhibitors that have beenapproved by the health authorities.

The class of aldosterone synthase inhibitors comprises compounds havingdiffering structural features. For example, mention may be made of thecompounds which are selected from the group consisting of thenon-steroidal aromatase inhibitors anastrozole, fadrozole (including the(+)-enantiomer thereof), as well as the steroidal aromatase inhibitorexemestane, or, in each case where applicable, a pharmaceuticallyacceptable salt thereof.

The most preferred non-steroidal aldosterone synthase inhibitor is the(+)-enantiomer of the hydrochloride of fadrozole (U.S. Pat. Nos.4,617,307 and 4,889,861) of formula

or a pharmaceutically acceptable alternate salt form thereof.

A preferred steroidal aldosterone receptor antagonist is eplerenone (cf.EP 122232 A) of the formula

or spironolactone.

The natriuretic peptides constitute a family of peptides that includethe atrial (ANP), brain-derived (BNP) and C-type natriuretic (CNP)peptides. The natriuretic peptides effect vasodilation, natriuresis,diuresis, decreased aldosterone release, decreased cell growth, andinhibition of the sympathetic nervous system and therenin-angiotensin-aldosterone system indicating their involvement in theregulation of blood pressure and of sodium and water balance. Neutralendopeptidase 24.11 (NEP) inhibitors impede degradation of natriureticpeptides and elicit pharmacological actions potentially beneficial inthe management of several cardiovascular disorders. A NEP inhibitoruseful in the said combination is an agent selected from the grouprepresented by candoxatril, sinorphan, SCH 34826 and SCH 42495.

Compounds having inhibitory effects on both angiotensin convertingenzyme and neutral endopetidase, so-called dual ACE/NEP inhibitors, canbe used for the treatment of cardiovascular pathologies. A preferreddual angiotensin converting enzyme/neutral endopetidase (ACE/NEP)inhibitor is, for example, omapatrilat (cf. EP 629627), fasidotril orfasidotrilat (cf. EP 419327), or Z 13752A (cf. WO 97/24342) or, ifappropriate, a pharmaceutically acceptable salt thereof.

Endothelin (ET) is a highly potent vasoconstrictor peptide synthesizedand released by the vascular endothelium. Endothelin (ET) exists inthree isoforms (ET-1, ET-2 and ET-3). (ET shall mean any or all of theisoforms of ET). Elevated levels of ET have been reported in plasma frompatients with e.g. essential hypertension. Endothelin receptorantagonists can be used to inhibit the vasoconstrictive effects inducedby ET.

A preferred endothelin antagonist is, for example, bosentan (cf. EP526708 A), enrasentan (cf. WO 94/25013), atrasentan (cf. WO 96/06095),especially atrasentan hydrochloride, darusentan (cf. EP 785926 A), BMS193884 (cf. EP 702012 A), sitaxsentan (cf. U.S. Pat. No. 5,594,021),especially sitaxsentan sodium, YM 598 (cf. EP 882719 A), S 0139 (cf. WO97/27314), J 104132 (cf. EP 714897 A or WO 97/37665), furthermore,tezosentan (cf. WO 96/19459), or in each case, a pharmaceuticallyacceptable salt thereof.

A diuretic is, for example, a thiazide derivative selected from thegroup consisting of chlorothiazide, hydrochlorothiazide,methylchlorothiazide, and chlorothalidon. The most preferred ishydrochlorothiazide.

Preferred are combinations, such as combined preparations orpharmaceutical compositions, respectively, comprising the DPP-IVinhibitor of formula (I) or a pharmaceutically accepted salt thereof andas second active agent an active agent selected from the groupconsisting of valsartan, benazepril, ramipril, lisinopril, enalapril,amlodipine, especially the besylate thereof, aliskiren, especially thehemifumarate thereof, atenolol, metoprolol, especially the hemi(R,R)fumarate or the fumarate thereof, oxprenolol, doxazosin, the (+)enantiomer of fadrozole, eplerenone, omapatrilat, Z 13752A, sitaxsentan,especially sitaxsentan sodium, darusentan and hydrochlorothiazide.

Furthermore preferred are combinations, such as a combined preparationsor pharmaceutical compositions, respectively, comprising the DPP-IVinhibitor of formula (I) or a pharmaceutically accepted salt thereof andone active agent selected from the group consisting of valsartan,benazepril, ramipril, lisinopril, enalapril, amlodipine, especially thebesylate thereof, aliskiren, especially the hemifumarate thereof,atenolol, metoprolol, especially the hemi (R,R)fumarate or the fumaratethereof, oxprenolol, doxazosin, the (+) enantiomer of fadrozole,eplerenone, omapatrilat, Z 13752A, sitaxsentan, especially sitaxsentansodium, and darusentan, furthermore comprising as third active agenthydrochlorothiazide.

The structure of the active agents identified by generic or tradenamesmay be taken from the actual edition of the standard compendium “TheMerck Index” or from databases, e.g. Patents International (e.g. IMSWorld Publications). The corresponding content thereof is herebyincorporated by reference. Any person skilled in the art is fullyenabled to identify the active agents and, based on these references,likewise enabled to manufacture and test the pharmaceutical indicationsand properties in standard test models, both in vitro and in vivo.

The corresponding active ingredients or a pharmaceutically acceptablesalts thereof may also be used in form of a solvate, such as a hydrateor including other solvents, used for crystallization.

The compounds to be combined can be present as pharmaceuticallyacceptable salts. If these compounds have, for example, at least onebasic center, they can form acid addition salts. Corresponding acidaddition salts can also be formed having, if desired, an additionallypresent basic center. The compounds having an acid group (for exampleCOOH) can also form salts with bases.

All the more surprising is the experimental finding that the combinedadministration of a DPP IV inhibitor or a salt thereof and a therapeuticagent selected from the group consisting of (i) to (xii) results notonly in a beneficial, especially a synergistic, therapeutic effect, butalso in additional benefits resulting from the combined treatment andfurther surprising beneficial effects compared to a monotherapy applyingonly one of the pharmaceutically active compounds used in thecombinations disclosed herein.

It can be shown by established test models and especially those testmodels described herein that the combination of the DPP-IV inhibitor offormula (I) with a therapeutic agent selected from the group consistingof (i) to (xii) results in a more effective prevention or preferablytreatment of diseases specified in the following. In particular, it canbe shown by established test models and especially those test modelsdescribed herein that the combination of the present invention resultsin a more effective prevention or preferably treatment of diseasesspecified hereinafter.

If taken simultaneously, this results not only in a further enhancedbeneficial, especially a synergistic, therapeutic effect, but also inadditional benefits resulting from the simultaneous treatment such as asurprising prolongation of efficacy, a broader variety of therapeutictreatment and surprising beneficial effects, e.g. less increase ofweight, on diseases and conditions associated with diabetes mellitus,for a number of combinations as described herein. Moreover, for a humanpatient, especially for elderly people, it is more convenient and easierto remember to take two tablets at the same time, e.g. before a meal,than staggered in time, i.e. according to a more complicated treatmentschedule. More preferably, both active ingredients are administered as afixed combination, i.e. as a single tablet, in all cases describedherein. Taking a single tablet is even easier to handle than taking twotablets at the same time. Furthermore, the packaging can be accomplishedwith less effort.

The person skilled in the pertinent art is fully enabled to select arelevant and standard animal test model to prove the hereinbefore andhereinafter indicated therapeutic indications and beneficial effects.

The pharmaceutical activities as effected by administration of theDPP-IV inhibitor of formula (I) or of the combination of the activeagents used according to the present invention can be demonstrated e.g.by using corresponding pharmacological models known in the pertinentart.

To evaluate the antihypertensive activity of the combination accordingto the invention, for example, the methodology as described by LovenbergW: Animal models for hypertension research. Prog. Clin. Biol. Res. 1987,229, 225-240 may be applied. For the evaluation that the combinationaccording to the present invention may be used for the treatment ofcongestive heart failure, for example, the methods as disclosed by SmithH J, Nuttall A: Experimental models of heart failure. Cardiovasc Res1985, 19, 181-186 may be applied. Also, rat models of hypertension andcardiac failure as described by Doggrell S A and Brown L (Cardiovasc Res1998, 39: 89-105) may be used for the pharmacological evaluation of thecombination. Molecular approaches such as transgenic methods are alsodescribed, for example by Luft et al.: Hypertension-induced end-organdamage. “A new transgenic approach for an old problem.” Hypertension1999, 33, 212-218.

The insulin secretion enhancing properties of the combination accordingto the present invention may be determined by following the methodologyas disclosed, for example, in the publication of T. Ikenoue et al. Biol.Pharm. Bull. 29(4), 354-359 (1997).

The simultaneous evaluation of the cardiovascular actions and of theglucose utilization effects of the agents given alone or in combinationcan be performed using models such as the Zucker fatty rat as describedin the publication of Nawano et al., Metabolism 48: 1248-1255, 1999.Also, studies using diabetic spontaneously hypertensive rats aredescribed in the publication of Sato et al., Metabolism 45:457-462,1996. Furthermore, rat models such as the Cohen-Rosenthal diabetichypertensive rat (Rosenthal et al., Hypertension. 1997;29:1260-1264) mayalso be used for the simultaneous assessments of the effects of thecombination on blood pressure and glucose metabolism.

The corresponding subject matter of these eight references is herewithincorporated by reference in this specification.

Accordingly, the combination according to the present invention may beused, e.g., for the prevention, delay of progression or treatment ofdiseases and disorders that may be inhibited by DPP IV inhibition, thatmay be inhibited by the enhancement of insulin secretion and that may beinhibited by insulin sensitization. Especially, the combinationaccording to the present invention may be used, e.g., for theprevention, delay of progression or treatment of diseases and disordersselected from the group consisting of hypertension (including but notlimited to isolated systolic hypertension and familial dyslipidemichypertension), congestive heart failure, left ventricular hypertrophy,peripheral arterial disease, diabetes, especially type 2 diabetesmellitus, diabetic retinopathy, macular degeneration, cataract, diabeticnephropathy, glomerulosclerosis, chronic renal failure, diabeticneuropathy, syndrome X, premenstrual syndrome, coronary heart disease,angina pectoris, thrombosis, atherosclerosis, myocardial infarction,transient ischemic attacks, stroke, vascular restenosis, hyperglycemia,hyperinsulinemia, hyperlipidemia, hypertryglyceridemia, insulinresistance, impaired glucose metabolism, conditions of impaired glucosetolerance, conditions of impaired fasting plasma glucose, obesity,erectile dysfunction, skin and connective tissue disorders, footulcerations and ulcerative colitis, endothelial dysfunction and impairedvascular compliance. Preferably, said combination may be used for thetreatment of hypertension, especially isolated systolic hypertension(ISH), congestive heart failure, endothelial dysfunction, impairedvascular compliance, impaired glucose tolerance and type II diabetesmellitus.

A “disease or condition which may be inhibited by a DPP-IV inhibitor” asdefined in this application comprises, but is not limited to insulinresistance, impaired glucose metabolism, conditions of impaired glucosetolerance, conditions of impaired fasting plasma glucose, obesity,diabetic retinopathy, macular degeneration, cataracts, diabeticnephropathy, glomerulosclerosis, diabetic neuropathy, erectiledysfunction, premenstrual syndrome, coronary heart disease,hypertension, angina pectoris, myocardial infarction, stroke, vascularrestenosis, skin and connective tissue disorders, foot ulcerations andulcerative colitis, endothelial dysfunction and impaired vascularcompliance.

Hypertension, in connection with a “disease or condition which may beinhibited by a cardiovascular compound [selected from the group(i)-(xii)]”, a “disease or condition which may be inhibited by theenhancement of insulin secretion” includes and is not limited to mild,moderate and severe hypertension as defined in Journal of Hypertension1999, 17:151-183, especially on page 162. Especially preferred is ISH.ISH is the most common form of hypertension in people over 50 years. Itis defined as elevated systolic blood pressure (above 140 mm Hg) inconjunction with normal diastolic blood pressure (below 90 mm Hg).Elevated systolic blood pressure is an independent risk factor forcardiovascular diseases and may lead e.g. to myocardial hypertrophy andheart failure. ISH is furthermore characterized by an increased pulsepressure, defined as the difference between systolic and diastolic bloodpressures. Elevated pulse pressure is being recognized as the type ofhypertension the least likely to be well controlled. A reduction ofelevated systolic blood pressure and correspondingly of pulse pressureis associated with a significant risk reduction in cardiovascular death.It has surprisingly been found that the combination of a DPP-IVinhibitor and a cardiovascular compound, as described in the presentinvention, leads to a decrease of ISH and pulse rate, both inhypertensive patients having type 2 diabetes mellitus and inhypertensive patients that do not have type 2 diabetes mellitus.

The term “prevention” means prophylactic administration of thecombination to healthy patients to prevent the outbreak of theconditions mentioned herein. Moreover, the term “prevention” meansprophylactic administration of such combination to patients being in apre-stage of the conditions, to be treated.

The term “delay of progression” used herein means administration of thecombination, such as a combined preparation or pharmaceuticalcomposition, to patients being in a pre-stage of the condition to betreated in which patients a pre-form of the corresponding condition isdiagnosed. Included is ‘prehypertension’ with ‘compelling indications’as defined in the JNC 7 Report (JAMA 2003, 289:2560-2572).Prehypertension is defined as systolic blood pressure ranging from120-139 mm Hg or diastolic blood pressure ranging from 80-89 mm Hg.

By the term “treatment” is understood the management and care of apatient for the purpose of combating the disease, condition, ordisorder.

Preferably, the jointly therapeutically effective amounts of the activeagents according to the combination of the present invention can beadministered simultaneously or sequentially in any order, e.g.separately or in a fixed combination.

Under certain circumstances, drugs with different mechanisms of actionmay be combined. However, just considering any combination of drugshaving different modes of action but acting in the similar field doesnot necessarily lead to combinations with advantageous effects.

All the more surprising is the experimental finding that the combinedadministration of a DPP-IV inhibitor according to the present invention,or, in each case, a pharmaceutically acceptable form thereof, resultsnot only in a beneficial, especially a potentiating or a synergistic,therapeutic effect. Independent thereof, additional benefits resultingfrom combined treatment can be achieved such as a surprisingprolongation of efficacy, a broader variety of therapeutic treatment andsurprising beneficial effects on diseases and conditions associated withdiabetes, e.g. less gain of weight. An additional and preferred aspectof the present invention is the prevention, delay of progression ortreatment of the condition of isolated systolic hypertension andimpaired vascular compliance which means decreased vascular elasticity.

The term “potentiation” shall mean an increase of a correspondingpharmacological activity or therapeutical effect, respectively.Potentiation of one component of the combination according to thepresent invention by co-administration of another component according tothe present invention means that an effect is being achieved that isgreater than that achieved with one component alone.

The term “synergistic” shall mean that the drugs, when taken together,produce a total joint effect that is greater than the sum of the effectsof each drug when taken alone.

The diseases, disorders or conditions related to type 2 diabetesmellitus, includes but are not limited to diabetic nephropathy, diabeticretinopathy and diabetic neuropathy.

Furthermore, it has been found that the chronic co-administration ofeither an insulin sensitizer or an insulin secretion enhancer impartsthe beneficial effect on blood vessel morphology and function andresults in a decrease of vascular stiffness and correspondingly in amaintenance and in an improvement of vascular compliance.

Accordingly, it has been found that the addition of a DPP-IV inhibitorto that of a cardiovascular compound would potentiate the effect onsystolic blood pressure and further improve vascularstiffness/compliance. Conversely, the proven antihypertensive effects ofa cardiovascular compound on systolic and diastolic blood pressure maybe potentiated by the addition of a DPP-IV inhibitor. The benefit ofthese combinations may also extend to an additional or potentiatedeffect on endothelial function, and improve vascular function andstructure in various organs/tissues including the kidney, heart, eye andbrain. Through the reduction in glucose levels, an anti-thrombotic andanti-atherosclerotic effect can also be demonstrated. Reduction ofglucose would prevent or minimize the glycosylation of any structural orfunctional protein within the cardio-renal system. This effect proves tobe highly beneficial by evoking an additive or synergistic effect onvascular function/structure when administered with DPP-IV inhibitorwhich alone improves cardiovascular function and structure through adistinct mechanism.

Additionally, insulin resistance may contribute, in part, to thedevelopment of diabetes, hypertension and atherosclerosis (Fukuda etal., 2001). It is known that angiotensin II impairs insulin signaling(Fukuda et al., 2001) and that interruption of the renin angiotensinsystem with the use of an ACE inhibitor can partially restore insulinsensitivity (Sato et al., 1996; Nawano et al., 1999). Insulin canproduce vasodilatation and lower blood pressure (Baron and Steinberg,1996). The Zucker fatty rat, an animal model with insulin resistance,has been shown to possess a significantly higher blood pressure(Alonso-Galicia et al., 1996). ACE inhibition lowers blood pressure andimproves insulin sensitivity in this model (Nawano et al., 1999).Combined administration of a cardiovascular compound as indicated in thepresent invention with a DPP-IV inhibitor will evoke furtherantihypertensive effects, improve vascular dynamics in hypertensivepatients to a greater extent than after administration of either agentgiven alone. Interestingly, the co-administration of a cardiovascularcompound and a DPP IV inhibitor will partially restore insulinsensitivity by preventing renin angiotensin system-induced impairment ofinsulin signaling pathways while at the same time raise insulin levelsand improve glucose utilization. Consequently, combined administrationwill simultaneously improve both the metabolic and cardiovascularabnormalities, two conditions that often coexist in patients.

Further benefits are that lower doses of the individual drugs to becombined according to the present invention can be used to reduce thedosage, for example, that the dosages need not only often be smaller butare also applied less frequently, or can be used in order to diminishthe incidence of side effects. This is in accordance with the desiresand requirements of the patients to be treated.

For example, it has turned out that the combination according to thepresent invention provides benefit especially in the treatment of modesthypertension or ISH that is beneficial to all diabetic patientsregardless of their hypertensive status, e.g. reducing the risk ofnegative cardiovascular events-by two different modes of action.

The DPP-IV inhibitor according to the present invention has proven to beuseful in the treatment of type 2 diabetes mellitus and can likewise beused for the reduction of blood pressure in for example improvingmicroalbuminuria. At sub-therapeutic doses, with respect to thetreatment of hypertension, the combination according to the inventionmay be merely used for the treatment of diabetes, especially type 2diabetes mellitus. In view of reduced dose of the DPP-IV inhibitor usedaccording to the present invention, there is a considerable safetyprofile of the combination making it suitable for first line therapy.

Further benefits when applying the composition of the present inventionare that lower doses of the individual drugs to be combined according tothe present invention can be used to reduce the dosage, for example,that the dosages need not only often be smaller but are also appliedless frequently, or can be used in order to diminish the incidence ofside effects. This is in accordance with the desires and requirements ofthe patients to be treated.

Preferably, the jointly therapeutically effective amounts of the activeagents according to the combination of the present invention can beadministered simultaneously or sequentially in any order, separately orin a fixed combination.

The pharmaceutical activities as effected by administration of thecombination of active agents used according to the present invention canbe demonstrated e.g. by using corresponding pharmacological models knownin the pertinent art. The person skilled in the pertinent art is fullyenabled to select a relevant animal test model to prove the hereinbeforeand hereinafter indicated therapeutic indications and beneficialeffects.

To evaluate the antihypertensive activity of the combination accordingto the invention, for example, the methodology as described by LovenbergW: Animal models for hypertension research. Prog. Clin. Biol. Res. 1987,229, 225-240 may be applied. For the evaluation that the combinationaccording to the present invention may be used for the treatment ofcongestive heart failure, for example, the methods as disclosed by SmithH J, Nuttall A: Experimental models of heart failure. Cardiovasc Res1985, 19, 181-186 may be applied. Molecular approaches such astransgenic methods are also described, for example by Luft et al.:Hypertension-induced end-organ damage. “A new transgemic approach for anold problem.” Hypertension 1999, 33, 212-218.

The insulin secretion enhancing properties of the combination accordingto the present invention may be determined by following the methodologyas disclosed, for example, in the publication of T. Ikenoue et al. Biol.Pharm. Bull. 29(4), 354-359 (1997).

The corresponding subject matter of these references is herewithincorporated by reference in this specification.

The pharmaceutical composition according to the present invention asdescribed herein before and hereinafter may be used for simultaneous useor sequential use in any order, for separate use or as a fixedcombination.

Accordingly, the invention furthermore relates to a method for theprevention of, delay of progression of, treatment of a disease orcondition selected from the group consisting of

(a) type 2 diabetes mellitus and related diseases, disorders orconditions (including but not limited to diabetic nephropathy, diabeticretinopathy and diabetic neuropathy);

(b) insulin resistance and syndrome X, obesity

(c) hypertension including hypertension in the elderly, familialdyslipidemic hypertension and isolated systolic hypertension (ISH);increased collagen formation, fibrosis, and remodeling followinghypertension (antiproliferative effect of the combination); erectiledysfunction, impaired vascular compliance, stroke; all these diseases orconditions associated with or without hypertension,

(d) congestive heart failure, left ventricular hypertrophy, survivalpost myocardial infarction (MI), coronary artery diseases,atherosclerosis, angina pectoris, thrombosis,

(e) renal failure, especially chronic renal failure, glomerulosclerosis,nephropathy;

(f) hypothyroidism;

(g) endothelial dysfunction with or without hypertension,

(h) hyperlipidemia, hyperlipoproteinemia, hypertryglyceridemia, andhypercholesterolemia,

(i) macular degeneration, cataract, glaucoma,

(j) skin and connective tissue disorders, and

(k) restenosis after percutaneous transluminal angioplasty, andrestenosis after coronary artery bypass surgery; peripheral vasculardisease;

comprising administering to a warm-blooded animal, including man, inneed thereof a jointly effective amount of a combination of a DPP IVinhibitor or a pharmaceutically acceptable salt thereof with at leastone therapeutic agent selected from the group consisting of

(i) an AT₁-receptor antagonist or a pharmaceutically acceptable saltthereof,

(ii) an angiotensin converting enzyme (ACE) inhibitor or apharmaceutically acceptable salt thereof,

(iii) a renin inhibitor or a pharmaceutically acceptable salt thereof,

(iv) a beta adrenergic receptor blocker or a pharmaceutically acceptablesalt thereof,

(v) an alpha adrenergic receptor blocker or a pharmaceuticallyacceptable salt thereof,

(vi) a calcium channel blocker or a pharmaceutically acceptable saltthereof,

(vii) an aldosterone synthase inhibitor or a pharmaceutically acceptablesalt thereof,

(viii) an aldosterone receptor antagonist or a pharmaceuticallyacceptable salt thereof,

(ix) a neutral endopeptidase (NEP) inhibitor or a pharmaceuticallyacceptable salt thereof,

(x) a dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP)inhibitor or a pharmaceutically acceptable salt thereof,

(xi) an endothelin receptor antagonist or a pharmaceutically acceptablesalt thereof, and

(xii) a diuretic or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention relates to the use of a combinationof a DPP IV inhibitor or a pharmaceutically acceptable salt thereof withat least one therapeutic agent selected from the group consisting of

(i) an AT₁-receptor antagonist or a pharmaceutically acceptable saltthereof,

(ii) an angiotensin converting enzyme (ACE) inhibitor or apharmaceutically acceptable salt thereof,

(iii) a renin inhibitor or a pharmaceutically acceptable salt thereof,

(iv) a beta adrenergic receptor blocker or a pharmaceutically acceptablesalt thereof,

(v) an alpha adrenergic receptor blocker or a pharmaceuticallyacceptable salt thereof,

(vi) a calcium channel blocker or a pharmaceutically acceptable saltthereof,

(vii) an aldosterone synthase inhibitor or a pharmaceutically acceptablesalt thereof,

(viii) an aldosterone receptor antagonist or a pharmaceuticallyacceptable salt thereof,

(ix) a neutral endopeptidase (NEP) inhibitor or a pharmaceuticallyacceptable salt thereof,

(x) a dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP)inhibitor or a pharmaceutically acceptable salt thereof,

(xi) an endothelin receptor antagonist or a pharmaceutically acceptablesalt thereof, and

(xii) a diuretic or a pharmaceutically acceptable salt thereof;

for the manufacture of a medicament for the prevention of, delay ofprogression of, or treatment of a disease or condition selected from thegroup consisting of

(a) type 2 diabetes mellitus and related diseases, disorders orconditions (including but not limited to diabetic nephropathy, diabeticretinopathy and diabetic neuropathy);

(b) insulin resistance and syndrome X, obesity

(c) hypertension including hypertension in the elderly, familialdyslipidemic hypertension, and isolated systolic hypertension (ISH);increased collagen formation, fibrosis, and remodeling followinghypertension (antiproliferative effect of the combination); erectiledysfunction, impaired vascular compliance, stroke; all these diseases orconditions associated with or without hypertension,

(d) congestive heart failure, left ventricular hypertrophy, survivalpost myocardial infarction (MI), coronary artery diseases,atherosclerosis, angina pectoris, thrombosis,

(e) renal failure, especially chronic renal failure, glomerulosclerosis,nephropathy;

(f) hypothyroidism;

(g) endothelial dysfunction with or without hypertension,

(h) hyperlipidemia, hyperlipoproteinemia, hypertryglyceridemia, andhypercholesterolemia,

(i) macular degeneration, cataract, glaucoma,

(j) skin and connective tissue disorders, and

(k) restenosis after percutaneous transluminal angioplasty, andrestenosis after coronary artery bypass surgery; peripheral vasculardisease;

The invention furthermore relates to a pharmaceutical composition forthe prevention of, delay of progression of, treatment of a disease orcondition selected from the group consisting of

(a) type 2 diabetes mellitus and related diseases, disorders orconditions (including but not limited to diabetic nephropathy, diabeticretinopathy and diabetic neuropathy);

(b) Insulin resistance and syndrome X, obesity;

(c) hypertension including hypertension in the elderly, familialdyslipidemic hypertension, and isolated systolic hypertension (ISH);increased collagen formation, fibrosis, and remodeling followinghypertension (antiproliferative effect of the combination); erectiledysfunction, impaired vascular compliance, stroke; all these diseases orconditions associated with or without hypertension;

(d) congestive heart failure, left ventricular hypertrophy, survivalpost myocardial infarction (MI), coronary artery diseases,atherosclerosis, angina pectoris, thrombosis;

(e) renal failure, especially chronic renal failure, glomerulosclerosis,nephropathy;

(f) hypothyroidism;

(g) endothelial dysfunction with or without hypertension;

(h) hyperlipidemia, hyperlipoproteinemia, hypertryglyceridemia, andhypercholesterolemia;

(i) macular degeneration, cataract, glaucoma;

(j) skin and connective tissue disorders, and

(k) restenosis after percutaneous transluminal angioplasty, andrestenosis after coronary artery bypass surgery; peripheral vasculardisease;

comprising a combination of a DPP IV inhibitor or a pharmaceuticallyacceptable salt thereof with at least one therapeutic agent selectedfrom the group consisting of

(i) an AT₁-receptor antagonist or a pharmaceutically acceptable saltthereof,

(ii) an angiotensin converting enzyme (ACE) inhibitor or apharmaceutically acceptable salt thereof,

(iii) a renin inhibitor or a pharmaceutically acceptable salt thereof,

(iv) a beta adrenergic receptor blocker or a pharmaceutically acceptablesalt thereof,

(v) an alpha adrenergic receptor blocker or a pharmaceuticallyacceptable salt thereof,

(vi) a calcium channel blocker or a pharmaceutically acceptable saltthereof,

(vii) an aldosterone synthase inhibitor or a pharmaceutically acceptablesalt thereof,

(viii) an aldosterone antagonist or a pharmaceutically acceptable saltthereof,

(ix) a neutral endopeptidase (NEP) inhibitor or a pharmaceuticallyacceptable salt thereof,

(x) a dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP)inhibitor or a pharmaceutically acceptable salt thereof,

(xi) an endothelin receptor antagonist or a pharmaceutically acceptablesalt thereof, and

(xii) a diuretic or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier.

Preferably, the jointly therapeutically effective amounts of the activeagents according to the combination of the present invention can beadministered simultaneously or sequentially in any order, separately orin a fixed combination.

The pharmaceutical composition according to the present invention asdescribed hereinbefore and hereinafter may be used for simultaneous useor sequential use in any order, for separate use or as a fixedcombination.

A further aspect of the present invention is a kit for the preventionof, delay of progression of, treatment of a disease or conditionaccording to the present invention comprising

(a) an amount of a DPP IV inhibitor or a pharmaceutically acceptablesalt thereof in a first unit dosage form;

(b) an amount of at least one therapeutic agent selected from the groupconsisting of components (i) to (xii), or, in each case, whereappropriate, a pharmaceutically acceptable salt thereof in a second etc.unit dosage form; and

(c) a container for containing said first, second etc. unit forms.

In a variation thereof, the present invention likewise relates to a“kit-of-parts”, for example, in the sense that the components to becombined according to the present invention can be dosed independentlyor by use of different fixed combinations with distinguished amounts ofthe components, i.e. simultaneously or at different time points. Theparts of the kit of parts can then e.g. be administered simultaneouslyor chronologically staggered, that is at different time points and withequal or different time intervals for any part of the kit of parts.Preferably, the time intervals are chosen such that the effect on thetreated disease or condition in the combined use of the parts is largerthan the effect that would be obtained by use of only any one of thecomponents.

The present invention thus also relates to a kit of parts comprising

(a) an amount of a DPP IV inhibitor or a pharmaceutically acceptablesalt thereof in a first unit dosage form;

(b) an amount of at least one therapeutic agent selected from the groupconsisting of components (i) to (xii), or, in each case, whereappropriate, a pharmaceutically acceptable salt thereof, in the form oftwo or three or more separate units of the components (i) to (xii).

The invention furthermore relates to a commercial package comprising thecombination according to the present invention together withinstructions for simultaneous, separate or sequential use.

In a preferred embodiment, the (commercial) product is a commercialpackage comprising as active ingredients the combination according tothe present invention (in the form of two or three or more separateunits of the components (i) to (xii)), together with instructions forits simultaneous, separate or sequential use, or any combinationthereof, in the delay of progression or treatment of the diseases (a) to(k) as mentioned herein.

All the preferences mentioned herein apply to the combination,composition, use, method of treatment, “kit of parts” and commercialpackage of the invention.

These pharmaceutical preparations are for enteral, such as oral, andalso rectal or parenteral, administration to homeotherms, with thepreparations comprising the pharmacological active compound either aloneor together with customary pharmaceutical auxiliary substances. Forexample, the pharmaceutical preparations consist of from about 0.1% to90%, preferably of from about 1% to about 80%, of the active compound.Pharmaceutical preparations for enteral or parenteral, and also forocular, administration are, for example, in unit dose forms, such ascoated tablets, tablets, capsules or suppositories and also ampoules.These are prepared in a manner that is known per se, for example usingconventional mixing, granulation, coating, solubulizing or lyophilizingprocesses. Thus, pharmaceutical preparations for oral use can beobtained by combining the active compound with solid excipients, ifdesired granulating a mixture which has been obtained, and, if requiredor necessary, processing the mixture or granulate into tablets or coatedtablet cores after having added suitable auxiliary substances.

The dosage of the active compound can depend on a variety of factors,such as mode of administration, homeothermic species, age and/orindividual condition.

Preferred dosages for the active ingredients of the pharmaceuticalcombination according to the present invention are therapeuticallyeffective dosages, especially those which are commercially available.

Normally, in the case of oral administration, an approximate daily doseof from about 1 mg to about 360 mg is to be estimated e.g. for a patientof approximately 75 kg in weight.

The dosage of the active compound can depend on a variety of factors,such as mode of administration, homeothermic species, age and/orindividual condition.

The pharmaceutical preparation will be supplied in the form of suitabledosage unit form, for example, a capsule or tablet, and comprising anamount, being together with the further component(s) jointly effective,e.g.

The doses of DPP-IV inhibitor of formula (I) to be administered towarm-blooded animals, for example human beings, of, for example,approximately 70 kg body weight, especially the doses effective in theinhibition of the enzyme renin, e.g. in lowering blood pressure and/orin improving the symptoms of glaucoma, are from approximately 3 mg toapproximately 3g, preferably from approximately 10 mg to approximately 1g, for example approximately from 20mg to 200mg, per person per day,divided preferably into 1 to 4 single doses which may, for example, beof the same size. Usually, children receive about half of the adultdose. The dose necessary for each individual can be monitored, forexample by measuring the serum concentration of the active ingredient,and adjusted to an optimum level. Single doses comprise, for example,10, 40 or 100 mg per adult patient.

Valsartan, as a representative of the class of AT₁-receptor antagonists,will be supplied in the form of suitable dosage unit form, for example,a capsule or tablet, and comprising a therapeutically effective amount,e.g. from about 20 to about 320 mg, of valsartan which may be applied topatients. The application of the active ingredient may occur up to threetimes a day, starting e.g. with a daily dose of 20 mg or 40 mg ofvalsartan, increasing via 80 mg daily and further to 160 mg daily up to320 mg daily. Preferably, valsartan is applied twice a day with a doseof 80 mg or 160 mg, respectively, each. Corresponding doses may betaken, for example, in the morning, at mid-day or in the evening.

Preferred dosage unit forms of ACE inhibitors are, for example, tabletsor capsules comprising e.g. from about 5 mg to about 40 mg, preferably 5mg, 10 mg, 20 mg or 40 mg, of benazepril; from about 6.5 mg to 100 mg,preferably 6.25 mg, 12.5 mg, 25 mg, 50 mg, 75 mg or 100 mg, ofcaptopril; from about 2.5 mg to about 40 mg, preferably 2.5 mg, 5 mg, 10mg, 20 mg or 40 mg, of enalapril; from about 10 mg to about 40 mg,preferably 10 mg or 20 mg, of fosinopril; from about 2 mg to about 8 mg,preferably 2 mg or 4 mg, of perindopril; from about 5 mg to about 40 mg,preferably 5 mg, 10 mg or 20 mg, of quinapril; or from about 1.25 mg toabout 20 mg, preferably 1.25 mg, 2.5 mg, or 5 mg, of ramipril.

Preferred dosage unit forms of renin inhibitors are, for example,tablets or capsules comprising e.g. from about 5 mg to about 500 mg,preferably, when using aliskiren, for example, 50 to 250 mg (equivalentto the free acid) of aliskiren, for example, administered once a day.

Preferred dosage unit forms of beta blockers are, for example, tabletsor capsules comprising e.g. from about 25 mg to 100 mg, especially 25mg, 50 mg or 100 mg, of atenolol; from about 2.5 to 10 mg, especially2.5 mg, 5 mg or 10 mg, of bisoprolol, especially the fumarate thereof;from about 50 to 200 mg, especially 50 mg, 100 mg or 200 mg, ofmetoprolol, especially the hemi-(R,R)-fumarate or the fumarate thereof;from about 100 mg to 2.5 g, especially 100 mg or 2.5 g, of esmolol,especially the hydrochloride thereof; 200 mg of celiprolol, especiallythe hydrochloride thereof; from about 50 mg to 100 mg, especially 50 mgor 100 mg, of talinolol; from about 200 mg to 800 mg, especially 200 mgor 400 mg, of acebutolol, especially the hydrochloride thereof; fromabout 10 mg to 30 mg, especially 10 mg or 20 mg, of timolol, especiallythe maleate thereof; from about 5 mg to 20 mg, especially 5 mg, 10 mg,or 20 mg of betaxolol, especially the hydrochloride thereof; from about20 mg to 80 mg, especially 20 mg, 40 mg, or 80 mg of nadolol, from about40 mg to 160 mg, especially, 40 mg, 80 mg or 160 mg, of oxprenolol,especially the hydrochloride thereof; from about 5 mg to 40 mg,especially, 5 mg, 10 mg, 20 mg or 40 mg, of pindolol; from about 25 mgto 160 mg, especially 25 mg, 40 mg, 80 mg, 100 mg or 160 mg, ofpropranolol, especially the hydrochloride thereof; from about 50 mg to100 mg, especially 50 mg or 100 mg, of bupranolol, especially thehydrochloride thereof; from about 2.5 to 40 mg, especially 2.5 mg, 5 mg,10 mg, 20 mg, or 40 mg of penbutolol, especially the sulphate thereof;from about 2.5 mg to 10 mg, especially 2.5 mg, 5 mg or 10 mg, ofcarteolol, especially the hydrochloride thereof; from about 3.125 mg to25 mg, especially 3.125 mg, 6.25 mg, 12.5 mg or 25 mg of carvedilol,from about 100 mg to 800 mg, especially 100 mg, 200 mg, 400 mg or 800 mgof labetalol, especially the hydrochloride thereof.

Preferably, in case of free combinations, preferred are those dosagesfor launched products that have been approved and that have beenmarketed.

Especially preferred are low dose combinations.

1 A pharmaceutical composition comprising a DPP IV inhibitor or apharmaceutically acceptable salt thereof and a cardiovascular compound,being different from a statin, or a pharmaceutically acceptable saltthereof. 2 The composition of claim 1 comprising a DPP IV inhibitor or apharmaceutically acceptable salt thereof and at least one therapeuticagent selected from the group consisting of (i) an AT₁-receptorantagonist or a pharmaceutically acceptable salt thereof, (ii) anangiotensin converting enzyme (ACE) inhibitor or a pharmaceuticallyacceptable salt thereof, (iii) a renin inhibitor or a pharmaceuticallyacceptable salt thereof, (iv) a beta adrenergic receptor blocker or apharmaceutically acceptable salt thereof, (v) an alpha adrenergicreceptor blocker or a pharmaceutically acceptable salt thereof, (vi) acalcium channel blocker or a pharmaceutically acceptable salt thereof,(vii) an aldosterone synthase inhibitor or a pharmaceutically acceptablesalt thereof, (viii) an aldosterone receptor antagonist or apharmaceutically acceptable salt thereof, (ix) a neutral endopeptidase(NEP) inhibitor or a pharmaceutically acceptable salt thereof, (x) adual angiotensin converting enzyme/neutral endopetidase (ACE/NEP)inhibitor or a pharmaceutically acceptable salt thereof, (xi) anendothelin receptor antagonist or a pharmaceutically acceptable saltthereof, and (xii) a diuretic or a pharmaceutically acceptable saltthereof. 3 The pharmaceutical composition of claim 1 wherein the DPP-IVinhibitor is(S)-1-{2-[5-cyanopyridin-2yl)amino]ethyl-aminoacetyl)-2-cyano-pyrrolidineor (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine. 4 Thepharmaceutical composition of claim 2, wherein the AT₁-receptorantagonist is losartan, olmesartan or valsartan; ACE inhibitor isbenazepril, enalapril, lisinopril or ramipril; renin inhibitor isaliskiren; beta blocker is metoprolol; alpha blocker is doxazosincalcium channel blocker is amlodipine; aldosterone synthase inhibitor isfadrozole or (+)-enantiomer of fadrozole; aldosterone receptorantagonist is eplerenone; neutral endopeptidase inhibitor is candoxatrilor sinorphan dual angiotensin converting enzyme/neutral endopetidase(ACE/NEP) inhibitor is omapatrilat; endothelin receptor antagonist isbosentan; diuretic is hydrochlorothiazide or, in each case, apharmaceutically acceptable salt thereof. 5 The pharmaceuticalcomposition of claim 1, comprising(S)-1-{2-[5-cyanopyridin-2yl)amino]ethyl-aminoacetyl)-2-cyano-pyrrolidineor (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine or apharmaceutically acceptable salt thereof and valsartan or apharmaceutically acceptable salt thereof or aliskiren or apharmaceutically acceptable salt thereof. 6 A method for the preventionof, delay of progression of, treatment of a disease or conditionselected from the group consisting of (a) type 2 diabetes mellitus andrelated diseases, disorders or conditions; (b) insulin resistance andsyndrome X, obesity; (c) hypertension including hypertension in theelderly, familial dyslipidemic hypertension, and isolated systolichypertension (ISH); increased collagen formation, fibrosis, andremodeling following hypertension; erectile dysfunction, impairedvascular compliance, stroke; all these diseases or conditions associatedwith or without hypertension; (d) congestive heart failure, leftventricular hypertrophy, survival post myocardial infarction (MI),coronary artery diseases, atherosclerosis, angina pectoris, thrombosis;(e) renal failure, especially chronic renal failure, glomerulosclerosis,nephropathy; (f) hypothyroidism; (g) endothelial dysfunction with orwithout hypertension; (h) hyperlipidemia, hyperlipoproteinemia,hypertryglyceridemia, and hypercholesterolemia; (i) maculardegeneration, cataract, glaucoma; (j) skin and connective tissuedisorders, and (k) restenosis after percutaneous transluminalangioplasty, and restenosis after coronary artery bypass surgery;peripheral vascular disease; comprising administering to a warm-bloodedanimal, including man, in need thereof a jointly effective amount of acombination of a DPP IV inhibitor or a pharmaceutically acceptable saltthereof with at least one therapeutic agent selected from the groupconsisting of (i) an AT₁-receptor antagonist or a pharmaceuticallyacceptable salt thereof, (ii) an angiotensin converting enzyme (ACE)inhibitor or a pharmaceutically acceptable salt thereof, (iii) a renininhibitor or a pharmaceutically acceptable salt thereof, (iv) a betaadrenergic receptor blocker or a pharmaceutically acceptable saltthereof, (v) an alpha adrenergic receptor blocker or a pharmaceuticallyacceptable salt thereof, (vi) a calcium channel blocker or apharmaceutically acceptable salt thereof, (vii) an aldosterone synthaseinhibitor or a pharmaceutically acceptable salt thereof, (viii) analdosterone receptor antagonist or a pharmaceutically acceptable saltthereof, (ix) a neutral endopeptidase (NEP) inhibitor or apharmaceutically acceptable salt thereof, (x) a dual angiotensinconverting enzyme/neutral endopetidase (ACE/NEP) inhibitor or apharmaceutically acceptable salt thereof, (xi) an endothelin receptorantagonist or a pharmaceutically acceptable salt thereof, and (xii) adiuretic or a pharmaceutically acceptable salt thereof. 7 (cancel) 8 Akit of parts comprising (a) an amount of a DPP IV inhibitor or apharmaceutically acceptable salt thereof in a first unit dosage form;(b) an amount of at least one therapeutic agent selected from the groupconsisting of (i) an AT₁-receptor antagonist or a pharmaceuticallyacceptable salt thereof, (ii) an angiotensin converting enzyme (ACE)inhibitor or a pharmaceutically acceptable salt thereof, (iii) a renininhibitor or a pharmaceutically acceptable salt thereof, (iv) a betaadrenergic receptor blocker or a pharmaceutically acceptable saltthereof, (v) an alpha adrenergic receptor blocker or a pharmaceuticallyacceptable salt thereof, (vi) a calcium channel blocker or apharmaceutically acceptable salt thereof, (vii) an aldosterone synthaseinhibitor or a pharmaceutically acceptable salt thereof, (viii) analdosterone receptor antagonist or a pharmaceutically acceptable saltthereof, (ix) a neutral endopeptidase (NEP) inhibitor or apharmaceutically acceptable salt thereof, (x) a dual angiotensinconverting enzyme/neutral endopetidase (ACE/NEP) inhibitor or apharmaceutically acceptable salt thereof, (xi) an endothelin receptorantagonist or a pharmaceutically acceptable salt thereof, and (xii) adiuretic or, in each case, where appropriate, a pharmaceuticallyacceptable salt thereof, in the form of two or three or more separateunits of the components (i) to (xii). 9 The pharmaceutical compositionof claim 2, wherein the DPP-IV inhibitor is(S)-1-{2-[5-cyanopyridin-2yl)amino]ethyl-aminoacetyl)-2-cyano-pyrrolidineor (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine, andwherein the AT₁-receptor antagonist is losartan, olmesartan orvalsartan; ACE inhibitor is benazepril, enalapril, lisinopril orramipril; renin inhibitor is aliskiren; beta blocker is metoprolol;alpha blocker is doxazosin calcium channel blocker is amlodipine;aldosterone synthase inhibitor is fadrozole or (+)-enantiomer offadrozole; aldosterone receptor antagonist is eplerenone; neutralendopeptidase inhibitor is candoxatril or sinorphan dual angiotensinconverting enzyme/neutral endopetidase (ACE/NEP) inhibitor isomapatrilat; endothelin receptor antagonist is bosentan; diuretic ishydrochlorothiazide or, in each case, a pharmaceutically acceptable saltthereof. 10 The pharmaceutical composition of claim 2, comprising(S)-1-{2-[5-cyanopyridin-2yl)amino]ethyl-aminoacetyl)-2-cyano-pyrrolidineor (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine or apharmaceutically acceptable salt thereof and valsartan or apharmaceutically acceptable salt thereof or aliskiren or apharmaceutically acceptable salt thereof.